This grant application deals with the development of polyoxometalate-based (nonnucleoside) agents to inhibit or eliminate HIV-1, the causative agent in AIDS. The long term objectives of this research are to formulate drugs of this class that are highly potent and selective, minimally toxic, permeable to the blood brain barrier, and orally bioavailable. It is anticipated that such drugs would be less susceptible to engendering resistance in patients than AZT. The specific aims are severalfold. First, recently developed lead compounds, and in particular a polyoxometalate of formula, Si2W18Nb6O778- (1) and closely related complexes will be further developed. 1 exhibits high activity against HIV- 1 and no detectable toxicity in a variety of cell cultures, high selectivity (e.g. greater inhibition of HIV-1 reverse transcriptase (RT) than human DNA polymerases), and is well tolerated in mammals. Development of these and 5 other families of promising lead compounds in our program will entail (a) preparation of new salt forms including the use of physiologically occurring cations such as protonated basic amino acids (such cations are already known to minimize toxicity in key cell lines including human bone marrow cells), (b) preparation of compounds with covalently attached organic groups, and (c) assessment of the hydrolytic stability and quantification of the breakdown products under biological conditions by NMR and other physical methods. The other 5 families of promising lead compounds have the following formulas: Na16(TM)4(H2O)2(P2W15O56)2, (TM = ZnII, CoII, or CuII), Nb6O198- (MnII)XW11O39x-, Nb4W2O196-, and H2P2W12O4812-. Second, the covalent attachment of organic groups to the surfaces of lead polyoxometalate drugs will provide a vehicle for the rational and systematic alteration of basic physical, chemical, and biological properties of direct pertinence to the development of optimal anti-HIV-1 agents. Such pendant groups should lead directly to preparation of more hydrophobic polyoxometalates with higher levels of blood-brain barrier permeability, higher degrees of oral bioavailability (and in particular optimized g.i., transport), and mammalian tolerance. Third, recent work has clearly established a dual molecular basis of action of polyoxometalate-based anti-HIV-1 agents. They are potent inhibitors of HIV-1 RT, but more significantly, they are potent inhibitors of the binding/fusion of chronically infected lymphocytes with healthy uninfected cells. This cellular fusion process may be a major mechanism in the advancement of AIDS, and very few other anti-HIV-1 agents have demonstrable anti-fusion activity. Polyoxometalates also appear to affect virus entry into cells. The relationships between the molecular features (size, shape, charge density, atomic composition, presence or absence of property-altering surface groups, etc.) of the polyoxometalates and their impact on anti-binding/fusion activity, viral entry, and other physical and biochemical characteristics will be determined.